Endothelial barrier disorder in hereditary angioedema: molecular mechanisms and therapeutic implications.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of vascular leakage and tissue swelling. Although excessive bradykinin generation has long been considered the central pathogenic mechanism, increasing evidence indicates that endothelial cells play a decisive role in determining when and where vascular permeability occurs. This Review summarizes recent advances in endothelial biology relevant to HAE, highlighting how intercellular junctions, the endothelial glycocalyx, and dynamic endothelial activation states cooperatively regulate barrier integrity. Newly identified HAE subtypes caused by pathogenic variants that directly affect endothelial regulatory pathways further support endothelial dysfunction as a key disease mechanism beyond bradykinin excess. By integrating bradykinin-dependent and bradykinin-independent processes within an endothelial-centered framework, this Review proposes a revised conceptual model for HAE pathogenesis and discusses its implications for biomarker discovery and therapeutic strategies aimed at stabilizing the endothelial barrier.